5-180628862-T-C

Variant names:

• chr5-180628862-T-C
• rs383985
• NM_182925.5:c.1103+20A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_182925.5(FLT4):​c.1103+20A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0782 in 1,537,158 control chromosomes in the GnomAD database, including 5,450 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.067 (482 hom., cov: 31)
  • Exomes 𝑓: 0.079 (4968 hom.)
• Consequence: FLT4 NM_182925.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -4.07
• Publications: 13 publications found

Genes affected

FLT4 (HGNC:3767): (fms related receptor tyrosine kinase 4) This gene encodes a tyrosine kinase receptor for vascular endothelial growth factors C and D. The protein is thought to be involved in lymphangiogenesis and maintenance of the lymphatic endothelium. Mutations in this gene cause hereditary lymphedema type IA. [provided by RefSeq, Jul 2008]

FLT4 Gene-Disease associations (from GenCC):

• lymphatic malformation 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• capillary infantile hemangioma

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• congenital heart defects, multiple types, 7

  Inheritance: AD Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• lymphatic malformation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• tetralogy of fallot

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BP6: Variant 5-180628862-T-C is Benign according to our data. Variant chr5-180628862-T-C is described in ClinVar as Benign. ClinVar VariationId is 263018.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.114 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLT4	NM_182925.5	c.1103+20A>G		intron_variant	Intron 8 of 29	ENST00000261937.11	NP_891555.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLT4	ENST00000261937.11	c.1103+20A>G		intron_variant	Intron 8 of 29	1	NM_182925.5	ENSP00000261937.6

Frequencies

GnomAD3 genomes AF: 0.0675 AC: 10221 AN: 151418 Hom.: 482 Cov.: 31

Gnomad AFR AF: 0.0166

Gnomad AMI AF: 0.00881

Gnomad AMR AF: 0.0472

Gnomad ASJ AF: 0.141

Gnomad EAS AF: 0.122

Gnomad SAS AF: 0.0370

Gnomad FIN AF: 0.140

Gnomad MID AF: 0.0353

Gnomad NFE AF: 0.0873

Gnomad OTH AF: 0.0541

GnomAD2 exomes AF: 0.0728 AC: 16453 AN: 226054 AF XY: 0.0729

Gnomad AFR exome AF: 0.0177

Gnomad AMR exome AF: 0.0314

Gnomad ASJ exome AF: 0.140

Gnomad EAS exome AF: 0.122

Gnomad FIN exome AF: 0.130

Gnomad NFE exome AF: 0.0807

Gnomad OTH exome AF: 0.0754

GnomAD4 exome AF: 0.0793 AC: 109917 AN: 1385626 Hom.: 4968 Cov.: 23 AF XY: 0.0788 AC XY: 54509 AN XY: 692172

African (AFR) AF: 0.0143 AC: 460 AN: 32162

American (AMR) AF: 0.0338 AC: 1496 AN: 44216

Ashkenazi Jewish (ASJ) AF: 0.135 AC: 3340 AN: 24692

East Asian (EAS) AF: 0.132 AC: 5182 AN: 39138

South Asian (SAS) AF: 0.0396 AC: 3291 AN: 83010

European-Finnish (FIN) AF: 0.124 AC: 5626 AN: 45308

Middle Eastern (MID) AF: 0.0381 AC: 174 AN: 4566

European-Non Finnish (NFE) AF: 0.0814 AC: 85831 AN: 1054676

Other (OTH) AF: 0.0781 AC: 4517 AN: 57858

GnomAD4 genome AF: 0.0674 AC: 10219 AN: 151532 Hom.: 482 Cov.: 31 AF XY: 0.0680 AC XY: 5035 AN XY: 74024

African (AFR) AF: 0.0165 AC: 681 AN: 41310

American (AMR) AF: 0.0471 AC: 718 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.141 AC: 489 AN: 3464

East Asian (EAS) AF: 0.122 AC: 622 AN: 5118

South Asian (SAS) AF: 0.0374 AC: 180 AN: 4808

European-Finnish (FIN) AF: 0.140 AC: 1480 AN: 10534

Middle Eastern (MID) AF: 0.0310 AC: 9 AN: 290

European-Non Finnish (NFE) AF: 0.0873 AC: 5914 AN: 67746

Other (OTH) AF: 0.0559 AC: 118 AN: 2110

Alfa AF: 0.0988 Hom.: 1932

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.51
DANN	Benign	0.10
PhyloP100		-4.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs383985; hg19: chr5-180055862; COSMIC: COSV56101064;